Hydroxymethyl ether hydroisoindoline tachykinin receptor antagonists

ABSTRACT

The present invention is directed to certain hydroxymethyl ether hydroisoindoline compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, LUTS, depression, and anxiety.

BACKGROUND OF THE INVENTION

Substance P is a naturally occurring undecapeptide belonging to thetachykinin family of peptides, the latter being so-named because oftheir prompt contractile action on extravascular smooth muscle tissue.The tachykinins are distinguished by a conserved carboxyl-terminalsequence. In addition to substance P, the known mammalian tachykininsinclude neurokinin A and neurokinin B. The current nomenclaturedesignates the receptors for substance P, neurokinin A, and neurokinin Bas neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3),respectively.

Tachykinin, and in particular substance P, antagonists are useful in thetreatment of clinical conditions which are characterized by the presenceof an excess of tachykinin, in particular substance P, activity,including disorders of the central nervous system, nociception and pain,gastrointestinal disorders, disorders of bladder function andrespiratory diseases.

SUMMARY OF THE INVENTION

The present invention is directed to certain hydroxymethyl etherhydroisoindoline compounds of Formula (I) which are useful asneurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykininand in particular substance P. The invention is also concerned withpharmaceutical formulations comprising these compounds as activeingredients and the use of the compounds and their formulations in thetreatment of certain disorders, including emesis, urinary incontinence,LUTS, depression, and anxiety.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment the present invention is directed to compounds of theformula I:

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof, wherein:R¹ is selected from the group consisting of:

(1) hydrogen,

(2) C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl,

(3) cyclopentenone, which is unsubstituted or substituted with hydroxyl,

(4) —(CO)—C₁₋₆alkyl,

(5) —(CO)—NH₂,

(6) —(CO)—NHC₁₋₆alkyl,

(7) —(CO)—N(C₁₋₆alkyl)(C₁₋₆alkyl),

(8) —(CO)—O—C₁₋₆alkyl,

(9) —(CO)—C₃₋₆cycloalkyl, and

X is independently selected from the group consisting of:

(1) hydrogen, and

(2) fluorine;

Y is independently selected from the group consisting of:

(1) hydrogen, and

(2) methyl;

Z is independently selected from the group consisting of:

(1) hydrogen,

(2) C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl,

(3) —(CO)—C₁₋₆alkyl,

(4) —(CO)-Aryl

(5) —(CO)O—C₁₋₆alkyl,

(6) —(CO)—NH₂,

(7) —(CO)—NHC₁₋₆alkyl, and

(8) —(CO)—N(C₁₋₆alkyl)(C₁₋₆alkyl),

wherein the alkyl portion of choices (4), (7) and (8) of R1 areoptionally substituted with halo, hydroxyl or phenyl.

Within this embodiment, there is a genus of compounds of the Formula Iaand Ib:

wherein R¹, X, Y and Z are defined herein,and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Within this embodiment there is sub-genus of compounds of Formulae (I),(Ia) and (Ib) wherein

R¹ is selected from the group consisting of:

(1) hydrogen,

(2) C₁₋₃alkyl, which is unsubstituted or substituted with hydroxyl orphenyl,

(3) cyclopent-2-en-1-one, which is unsubstituted or substituted withhydroxyl,

(4) —(CO)—C₁₋₃alkyl,

(5) —(CO)—NH₂,

(6) —(CO)—NHC₁₋₃alkyl,

(7) —(CO)—N(C₁₋₃alkyl)(C₁₋₃alkyl), and

wherein the alkyl portion of choices (4), (6) and (7) of R1 areoptionally substituted with halo, hydroxyl or phenyl.

Within this sub-genus there is a class herein R¹ is selected from thegroup consisting of:

(1) hydrogen,

(2) cyclopent-2-en-1-one,

(3) 1,2-oxazol-4(5H)-one,

(4) 2,2-dimethylpropanoyl,

(5) methylpropanoyl,

(6) CH₃NH—(CO)—, and

(7) (CH₃)₂—N—(CO)—.

Within this class there is a sub-class wherein R¹ is hydrogen.

Within this class there is another sub-class wherein R¹ is:

Within this class there is another sub-class wherein R¹ is:

Within this class there is a sub-class wherein R¹ is CH₃NH—(CO)—, or(CH₃)₂—N—(CO)—.

Within this embodiment there is a genus of compounds wherein Z isselected from the group consisting of

(1) hydrogen,

(2) C₁₋₃alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl,

(3) —(CO)-phenyl, and

(4) —(CO)O-methyl.

Within this embodiment there is sub-genus of compound of Formulae (I),(Ia) and

(Ib) wherein X is hydrogen. Within this embodiment there is sub-genus ofcompound of Formulae (I), (Ia) and (Ib) wherein X is fluorine.

Within this embodiment there is a genus of compounds of formula Ia orIb:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof whereinR¹ is selected from the group consisting of:

(1) hydrogen,

(2) cyclopent-2-en-1-one,

(3) 1,2-oxazol-4(5H)-one,

(4) 2,2-dimethylpropanoyl,

(5) methylpropanoyl,

(6) CH₃NH—(CO)—,

(7) (CH₃)₂—N—(CO)—, and

X is independently selected from the group consisting of:

(1) hydrogen, and

(2) fluorine;

Y is independently selected from the group consisting of:

(1) hydrogen, and

(2) methyl;

Z is independently selected from the group consisting of:

(1) hydrogen,

(2) C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl,

(3) —(CO)—C₁₋₆alkyl,

(4) —(CO)-Aryl

(5) —(CO)O—C₁₋₆alkyl,

(6) —(CO)—NH₂,

(6) —(CO)—NHC₁₋₆alkyl, and

(7) —(CO)—N(C₁₋₆alkyl)(C₁₋₆alkyl),

Within this genus there is a sub-genus of compounds wherein Z isselected from the group consisting of

(1) hydrogen,

(2) C₁₋₃alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl,

(3) —(CO)-phenyl, and

(4) —(CO)O-methyl.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.

Within this embodiment there is sub-genus of compound of Formulae (I),(Ia) and (Ib) wherein Y is hydrogen. Within this embodiment there isanother sub-genus of compound of Formulae (I), (Ia) and (Ib) wherein Yis methyl.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.

Within this embodiment there is sub-genus of compound of Formulae (I),(Ia) and (Ib) wherein Z is hydrogen. Within this embodiment there isanother sub-genus of compound of Formulae (I), (Ia) and (Ib) wherein Zis methyl.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without preferredstereochemistry. The independent syntheses of these diastereomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

There are several acceptable methods of naming the compounds discussedherein.

For example, the above compound can be named either as “(3aR,4R,5S,7aR)tert-butyl-5-hydroxy-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate”or “tert-butyl(3aR,4R,5S,7aR)-5-hydroxy-4-phenyloctahydro-2H-isoindole-2-carboxylate”.The core structure may be generally referred to as octahydroisoindole,hexahydroisoindoline, perhydroisoindoline, hydroisoindoline, orhydroisoindole compounds.

As appreciated by those of skill in the art, halo or halogen as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₈alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like. When the compound of thepresent invention is basic, salts may be prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic and organic acids. Suchacids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid, and the like. Particularly preferred are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of the present invention are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The compounds of the present invention are useful in the prevention andtreatment of a wide variety of clinical conditions which arecharacterized by the presence of an excess of tachykinin, in particularsubstance P, activity. Thus, for example, an excess of tachykinin, andin particular substance P, activity is implicated in a variety ofdisorders of the central nervous system. Such disorders include mooddisorders, such as depression or more particularly depressive disorders,for example, single episodic or recurrent major depressive disorders anddysthymic disorders, or bipolar disorders, for example, bipolar Idisorder, bipolar II disorder and cyclothymic disorder; anxietydisorders, such as panic disorder with or without agoraphobia,agoraphobia without history of panic disorder, specific phobias, forexample, specific animal phobias, social phobias, obsessive-compulsivedisorder, stress disorders including post-traumatic stress disorder andacute stress disorder, and generalised anxiety disorders; schizophreniaand other psychotic disorders, for example, schizophreniform disorders,schizoaffective disorders, delusional disorders, brief psychoticdisorders, shared psychotic disorders and psychotic disorders withdelusions or hallucinations; delerium, dementia, and amnestic and othercognitive or neurodegenerative disorders, such as Alzheimer's disease,senile dementia, dementia of the Alzheimer's type, vascular dementia,and other dementias, for example, due to HIV disease, head trauma,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jakob disease, or due to multiple etiologies; Parkinson'sdisease and other extra-pyramidal movement disorders such asmedication-induced movement disorders, for example, neuroleptic-inducedparkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia and medication-induced postural tremor;substance-related disorders arising from the use of alcohol,amphetamines (or amphetamine-like substances) caffeine, cannabis,cocaine, hallucinogens, inhalants and aerosol propellants, nicotine,opioids, phenylglycidine derivatives, sedatives, hypnotics, andanxiolytics, which substance-related disorders include dependence andabuse, intoxication, withdrawal, intoxication delerium, withdrawaldelerium, persisting dementia, psychotic disorders, mood disorders,anxiety disorders, sexual dysfunction and sleep disorders; epilepsy;Down's syndrome; demyelinating diseases such as MS and ALS and otherneuropathological disorders such as peripheral neuropathy, for examplediabetic and chemotherapy-induced neuropathy, and postherpeticneuralgia, trigeminal neuralgia, segmental or intercostal neuralgia andother neuralgias; and cerebral vascular disorders due to acute orchronic cerebrovascular damage such as cerebral infarction, subarachnoidhemorrhage or cerebral oedema.

Tachykinin, and in particular substance P, activity is also involved innociception and pain. The compounds of the present invention willtherefore be of use in the prevention or treatment of diseases andconditions in which pain predominates, including soft tissue andperipheral damage, such as acute trauma, osteoarthritis, rheumatoidarthritis, musculo-skeletal pain, particularly after trauma, spinalpain, myofascial pain syndromes, headache, episiotomy pain, and burns;deep and visceral pain, such as heart pain, muscle pain, eye pain,orofacial pain, for example, odontalgia, abdominal pain, gynecologicalpain, for example, dysmenorrhea, and labour pain; pain associated withnerve and root damage, such as pain associated with peripheral nervedisorders, for example, nerve entrapment and brachial plexus avulsions,amputation, peripheral neuropathies, tic douloureux, atypical facialpain, nerve root damage, and arachnoiditis; pain associated withcarcinoma, often referred to as cancer pain; central nervous systempain, such as pain due to spinal cord or brain stem damage; low backpain; sciatica; ankylosing spondylitis, gout; and scar pain.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of respiratory diseases, particularly thoseassociated with excess mucus secretion, such as chronic obstructiveairways disease, bronchopneumonia, chronic bronchitis, cystic fibrosisand asthma, adult respiratory distress syndrome, and bronchospasm;inflammatory diseases such as inflammatory bowel disease, psoriasis,fibrositis, osteoarthritis, rheumatoid arthritis, pruritus and sunburn;allergies such as eczema and rhinitis; hypersensitivity disorders suchas poison ivy; ophthalmic diseases such as conjunctivitis, vernalconjunctivitis, and the like; ophthalmic conditions associated with cellproliferation such as proliferative vitreoretinopathy; cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of neoplasms, including breast tumours,neuroganglioblastomas and small cell carcinomas such as small cell lungcancer.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of gastrointestinal (GI) disorders, includinginflammatory disorders and diseases of the GI tract such as gastritis,gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disordersassociated with the neuronal control of viscera, ulcerative colitis,Crohn's disease, irritable bowel syndrome and emesis, including acute,delayed or anticipatory emesis such as emesis induced by chemotherapy,radiation, toxins, viral or bacterial infections, pregnancy, vestibulardisorders, for example, motion sickness, vertigo, dizziness andMeniere's disease, surgery, migraine, variations in intercranialpressure, gastro-oesophageal reflux disease, acid indigestion, overindulgence in food or drink, acid stomach, waterbrash or regurgitation,heartburn, for example, episodic, nocturnal or meal-induced heartburn,and dyspepsia.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of a variety of other conditions including stressrelated somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; adverse immunological reactions such asrejection of transplanted tissues and disorders related to immuneenhancement or suppression such as systemic lupus erythematosus; plasmaextravasation resulting from cytokine chemotherapy, disorders of bladderfunction such as cystitis, bladder detrusor hyper-reflexia, frequenturination, urinary incontinence and LUTS, including the prevention ortreatment of overactive bladder with symptoms of urge urinaryincontinence, urgency, and frequency; fibrosing and collagen diseasessuch as scleroderma and eosinophilic fascioliasis; disorders of bloodflow caused by vasodilation and vasospastic diseases such as angina,vascular headache, migraine and Reynaud's disease; and pain ornociception attributable to or associated with any of the foregoingconditions, especially the transmission of pain in migraine.

As used herein, the term “urinary incontinence” is intended to include arange of conditions including urge incontinence, stress incontinence,overflow incontinence, functional incontinence, neurogenic incontinence,post-prostatectomy incontinence, urinary frequency, urinary urgency,nocturia, enuresis, and related conditions in mammalian subjects. Inmore detailed embodiments, the lower urinary tract disorder, or targetedsymptoms for treatment arising therefrom, may include overactivebladder, including neurogenic and non-neurogenic overactive bladder,interstitial cystitis, prostatitis, prostadynia, and benign prostatichyperplasia. In further embodiments, the methods and compositions of theinvention are effective for preventing or treating excessive micturitionin subjects suffering from lower urinary tract disorders.

The compounds of the present invention are also of value in thetreatment of a combination of the above conditions, in particular in thetreatment of combined post-operative pain and post-operative nausea andvomiting.

The compounds of the present invention are particularly useful in theprevention or treatment of emesis, including acute, delayed oranticipatory emesis, such as emesis induced by chemotherapy, radiation,toxins, pregnancy, vestibular disorders, motion, surgery, migraine, andvariations in intercranial pressure. For example, the compounds of thepresent invention are of use optionally in combination with otherantiemetic agents for the prevention of acute and delayed nausea andvomiting associated with initial and repeat courses of moderate orhighly emetogenic cancer chemotherapy, including high-dose cisplatin.Most especially, the compounds of the present invention are of use inthe treatment of emesis induced by antineoplastic (cytotoxic) agents,including those routinely used in cancer chemotherapy, and emesisinduced by other pharmacological agents, for example, rolipram. Examplesof such chemotherapeutic agents include alkylating agents, for example,ethyleneimine compounds, alkyl sulphonates and other compounds with analkylating action such as nitrosoureas, cisplatin and dacarbazine;antimetabolites, for example, folic acid, purine or pyrimidineantagonists; mitotic inhibitors, for example, vinca alkaloids andderivatives of podophyllotoxin; and cytotoxic antibiotics. Particularexamples of chemotherapeutic agents are described, for instance, by D.J. Stewart in Nausea and Vomiting: Recent Research and ClinicalAdvances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Fla.,USA (1991) pages 177-203, especially page 188. Commonly usedchemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine, streptozocin, cyclophosphamide,carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin),daunorubicin, procarbazine, mitomycin, cytarabine, etoposide,methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin andchlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984)68(1), 163-172].

A further aspect of the present invention comprises the use of acompound of the present invention for achieving a chronobiologic(circadian rhythm phase-shifting) effect and alleviating circadianrhythm disorders in a mammal. The present invention is further directedto the use of a compound of the present invention for blocking thephase-shifting effects of light in a mammal.

A further aspect of the present invention comprises the use of acompound of the present invention in the treatment of Lower urinarytract symptoms (LUTS). LUTS in men include, but are not, restricted to acomplex of obstructive (voiding) and irritative (storage or filling)symptoms, which include increased frequency, nocturia, poor urinarystream and hesitancy or delay in starting urinary flow. LUTS arerecognized as arising from changes in urethral resistance induced by theenlarging prostate as well as contraction of the prostatic smoothmuscle. The resulting increase in urethral resistance restricts theoutflow of urine and causes secondary changes are induced in thebladder. A characteristic pattern of unstable bladder contractions, alsoknown as irritable bladder, is often observed in men with morphologicalBPH.

The present invention is further directed to the use of a compound ofthe present invention or a pharmaceutically acceptable salt thereof, forenhancing or improving sleep quality as well as preventing and treatingsleep disorders and sleep disturbances in a mammal. In particular, thepresent invention provides a method for enhancing or improving sleepquality by increasing sleep efficiency and augmenting sleep maintenance.In addition, the present invention provides a method for preventing andtreating sleep disorders and sleep disturbances in a mammal whichcomprising the administration of a compound of the present invention ora pharmaceutically acceptable salt thereof. The present invention isuseful for the treatment of sleep disorders, including Disorders ofInitiating and Maintaining Sleep (insomnias) (“DIMS”) which can arisefrom psychophysiological causes, as a consequence of psychiatricdisorders (particularly related to anxiety), from drugs and alcohol useand abuse (particularly during withdrawal stages), childhood onset DIMS,nocturnal myoclonus and restless legs and non specific REM disturbancesas seen in ageing.

The particularly preferred embodiments of the instant invention are thetreatment of emesis, urinary incontinence, depression or anxiety byadministration of the compounds of the present invention to a subject(human or animal) in need of such treatment.

The present invention is directed to a method for the manufacture of amedicament for antagonizing the effect of substance P at its receptorsite or for the blockade of neurokinin-1 receptors in a mammalcomprising combining a compound of the present invention with apharmaceutical carrier or diluent. The present invention is furtherdirected to a method for the manufacture of a medicament for thetreatment of a physiological disorder associated with an excess oftachykinins in a mammal comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The present invention also provides a method for the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of the present invention or a compositioncomprising a compound of the present invention.

As used herein, the term “treatment” or “to treat” refers to theadministration of the compounds of the present invention to reduce,ameliorate, or eliminate either the symptoms or underlying cause of thenoted disease conditions, in a subject (human or animal) that suffersfrom that condition or displays clinical indicators thereof.

The term “prevention” or “to prevent” refers to the administration ofthe compounds of the present invention to reduce, ameliorate, oreliminate the risk or likelihood of occurrence of the noted diseaseconditions, in a subject (human or animal) susceptible or predisposed tothat condition.

The compounds of this invention are useful for antagonizing tachykinins,in particular substance P in the treatment of gastrointestinaldisorders, central nervous system disorders, inflammatory diseases, painor migraine and asthma in a mammal in need of such treatment. Thisactivity can be demonstrated by the following assays.

Receptor Expression in COS: To express the cloned human neurokinin-1receptor (NK1R) transiently in COS, the cDNA for the human NK1R wascloned into the expression vector pCDM9 which was derived from pCDM8(INVITROGEN) by inserting the ampicillin resistance gene (nucleotide1973 to 2964 from BLUESCRIPT SK+) into the Sac II site. Transfection of20 ug of the plasmid DNA into 10 million COS cells was achieved byelectroporation in 800 ul of transfection buffer (135 mM NaCl, 1.2 mMCaCl₂, 1.2 mM MgCl₂, 2.4 mM K₂HPO₄, 0.6 mM KH₂PO₄, 10 mM glucose, 10 mMHEPES pH 7.4) at 260 V and 950 uF using the IBI GENEZAPPER (1131, NewHaven, Conn.). The cells were incubated in 10% fetal calf serum, 2 mMglutamine, 100 U/ml penicillin-streptomycin, and 90% DMEM media (GIBCO,Grand Island, N.Y.) in 5% CO₂ at 37° C. for three days before thebinding assay.

Stable Expression in CHO: To establish a stable cell line expressing thecloned human NK1R, the cDNA was subcloned into the vector pRcCMV(INVITROGEN). Transfection of 20 ug of the plasmid DNA into CHO cellswas achieved by electroporation in 800 ul of transfection buffersupplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 uFusing the IBI GENEZAPPER (IBI). The transfected cells were incubated inCHO media [10% fetal calf serum, 100 U/ml penicillin-streptomycin, 2 mMglutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM media (JRHBIOSCIENCES, Lenexa, Kans.), 0.7 mg/ml G418 (GIBCO)] in 5% CO₂ at 37° C.until colonies were visible. Each colony was separated and propagated.The cell clone with the highest number of human NK1R was selected forsubsequent applications such as drug screening.

Assay Protocol using COS or CHO: The binding assay of human NK1Rexpressed in either COS or CHO cells is based on the use of¹²⁵I-substance P (¹²⁵I-SP, from DU PONT, Boston, Mass.) as aradioactively labeled ligand which competes with unlabeled substance Por any other ligand for binding to the human NK1R. Monolayer cellcultures of COS or CHO were dissociated by the non-enzymatic solution(SPECIALTY MEDIA, Lavallette, N.J.) and resuspended in appropriatevolume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl₂, 150 mMNaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01mM phosphoramidon) such that 200 ul of the cell suspension would giverise to about 10,000 cpm of specific ¹²⁵I-SP binding (approximately50,000 to 200,000 cells). In the binding assay, 200 ul of cells wereadded to a tube containing 20 ul of 1.5 to 2.5 nM of ¹²⁵I-SP and 20 ulof unlabeled substance P or any other test compound. The tubes wereincubated at 4° C. or at room temperature for 1 hour with gentleshaking. The bound radioactivity was separated from unboundradioactivity by GF/C filter (BRANDEL, Gaithersburg, Md.) which waspre-wetted with 0.1% polyethylenimine. The filter was washed with 3 mlof wash buffer (50 mM Tris pH 7.5, 5 mM MnCl₂, 150 mM NaCl) three timesand its radioactivity was determined by gamma counter. The activation ofphospholipase C by NK1R may also be measured in CHO cells expressing thehuman NK1R by determining the accumulation of inositol monophosphatewhich is a degradation product of IP₃. CHO cells are seeded in 12-wellplate at 250,000 cells per well. After incubating in CHO media for 4days, cells are loaded with 0.025 uCi/ml of 3H-myoinositol by overnightincubation. The extracellular radioactivity is removed by washing withphosphate buffered saline. LiCl is added to the well at finalconcentration of 0.1 mM with or without the test compound, andincubation is continued at 37° C. for 15 mM. Substance P is added to thewell at final concentration of 0.3 nM to activate the human NK1R. After30 min of incubation at 37° C., the media is removed and 0.1 N HCl isadded. Each well is sonicated at 4° C. and extracted with CHCl₃/methanol(1:1). The aqueous phase is applied to a 1 ml Dowex AG 1×8 ion exchangecolumn. The column is washed with 0.1 N formic acid followed by 0.025 Mammonium formate-0.1 N formic acid. The inositol monophosphate is elutedwith 0.2 M ammonium formate-0.1 N formic acid and quantitated by betacounter.

In particular, the intrinsic tachykinin receptor antagonist activitiesof the compounds of the present invention may be demonstrated by thisassay. The compounds of the invention have activity in theaforementioned assay in the range of 0.05 nM to 10 μM. The Exampleshereinunder were found to have the following activity:

Example IC50 (nM) 1 — 2 0.04 3 0.06 4 0.1 5 0.06 6 0.03 7 0.08 8 0.03 90.09 10 0.03 11 0.03 12 0.07 13 0.06 14 0.46 15 17 16 0.35 17 — 18 — 19— 20 — 21 55 22 2.2 23 2.1 24 45 25 3.1 26 59 27 47% at 0.1 nMThe activity of the present compounds may also be demonstrated by theassay disclosed by Lei, et al., British J. Pharmacol., 105, 261-262(1992).

According to a further or alternative aspect, the present inventionprovides a compound of the present invention for use as a compositionthat may be administered to a subject in need of a reduction of theamount of tachykinin or substance P in their body.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional carrier comprising inert ingredients, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. In general, pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Oilysuspensions may be formulated by suspending the active ingredient in asuitable oil. Oil-in-water emulsions may also be employed. Dispersiblepowders and granules suitable for preparation of an aqueous suspensionby the addition of water provide the active ingredient in admixture witha dispersing or wetting agent, suspending agent and one or morepreservatives.

Pharmaceutical compositions of the present compounds may be in the formof a sterile injectable aqueous or oleagenous suspension. The compoundsof the present invention may also be administered in the form ofsuppositories for rectal administration. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present invention may be employed. The compounds of thepresent invention may also be formulated for administered by inhalation.The compounds of the present invention may also be administered by atransdermal patch by methods known in the art.

The compositions containing compounds of the present invention may bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. The term “unit dosage form” is takento mean a single dose wherein all active and inactive ingredients arecombined in a suitable system, such that the patient or personadministering the drug to the patient can open a single container orpackage with the entire dose contained therein, and does not have to mixany components together from two or more containers or packages. Typicalexamples of unit dosage forms are tablets or capsules for oraladministration, single dose vials for injection, or suppositories forrectal administration. This list of unit dosage forms is not intended tobe limiting in any way, but merely to represent typical examples in thepharmacy arts of unit dosage forms.

The compositions containing compounds of the present invention may alsobe presented as a kit, whereby two or more components, which may beactive or inactive ingredients, carriers, diluents, and the like, areprovided with instructions for preparation of the actual dosage form bythe patient or person administering the drug to the patient. Such kitsmay be provided with all necessary materials and ingredients containedtherein, or they may contain instructions for using or making materialsor components that must be obtained independently by the patient orperson administering the drug to the patient.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” or “administering a” compound should beunderstood to mean providing a compound of the invention to theindividual in need of treatment in a form that can be introduced intothat individuals body in a therapeutically useful form andtherapeutically effective amount, including, but not limited to: oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelike; injectable dosage forms, such as IV, IM, or IP, and the like;transdermal dosage forms, including creams, jellies, powders, orpatches; buccal dosage forms; inhalation powders, sprays, suspensions,and the like; and rectal suppositories.

The term “therapeutically effective amount” refers to a sufficientquantity of the compounds of the present invention, in a suitablecomposition, and in a suitable dosage form to treat or prevent the noteddisease conditions.

The compounds of the present invention may be administered incombination with another substance that has a complimentary effect tothe tachykinin and substance P inhibitors of the present invention.

Accordingly, in the prevention or treatment of emesis, a compound of thepresent invention may be used in conjunction with other anti-emeticagents, especially 5HT₃ receptor antagonists, such as ondansetron,granisetron, tropisetron, palenosetron and zatisetron, a corticosteroid,such as dexamethasone, or GABA_(B) receptor agonists, such as baclofen.Likewise, for the prevention or treatment of migraine a compound of thepresent invention may be used in conjunction with other anti-migraineagents, such as ergotamines or 5HT₁ agonists, especially sumatriptan,naratriptan, zolmatriptan or rizatriptan.

It will be appreciated that for the treatment of depression or anxiety,a compound of the present invention may be used in conjunction withother anti-depressant or anti-anxiety agents, such as norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), α-adrenoreceptor antagonists, atypical anti-depressants,benzodiazepines, 5-HT_(1A) agonists or antagonists, especially 5-HT_(1A)partial agonists, corticotropin releasing factor (CRF) antagonists, andpharmaceutically acceptable salts thereof. For the treatment orprevention of eating disorders, including obesity, bulimia nervosa andcompulsive eating disorders, a compound of the present invention may beused in conjunction with other anorectic agents. It will be appreciatedthat for the treatment or prevention of pain or nociception orinflammatory diseases, a compound of the present invention may be usedin conjunction with an antiinflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, such as an inhibitor of5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor,an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non-steroidal antiinflammatory agent, or acytokine-suppressing antiinflammatory agent.

For the treatment of urinary incontinence and LUTS, a compound of theinvention may be used in combination with a β3 adrenergic receptor(β3AR) agonist (β3 agonist), and/or an anti-muscatinic and optionally analpha-1 adrenergic antagonist, or a steroid type II 5-alpha-reductaseinhibitor.

For purposes of this specification the β3 agonist is intended to includeN-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclopentylpropyl)-5-tetrazolon-1-yl]benzenesulfonamide;and2N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide.Appropriate daily amounts of the (β3 agonist include 10 mg, 25, mg, 50mg, 100 mg, 125 mg, 200 mg, 250 mg and 375 mg. These beta 3 agonists arediscussed and may be prepared as disclosed in U.S. Pat. No. 5,561,142and U.S. Pat. No. 6,011,048, which are hereby incorporated by reference.

For purposes of this specification, anti-muscarinic agents included, butare not limited to tolterodine, oxybutynin, trospium, vamicamide,solifenacin, propiverine, S-oxybutynin, temiverine, sanctura, staybla,fesoterodine, SVT40776, 202405 by GlaxoSmithKline, TD6301, RBX9841,DDP200, and PLD179. See, for example, U.S. Pat. No. 5,382,600; U.S. Pat.No. 3,176,019; U.S. Pat. No. 3,480,626; U.S. Pat. No. 4,564,621; U.S.Pat. No. 5,096,890; U.S. Pat. No. 6,017,927; U.S. Pat. No. 6,174,896;U.S. Pat. No. 5,036,098; U.S. Pat. No. 5,932,607; U.S. Pat. No.6,713,464; U.S. Pat. No. 6,858,650; and DD 106643. See also, U.S. Pat.No. 6,103,747; U.S. Pat. No. 6,630,162; U.S. Pat. No. 6,770,295; U.S.Pat. No. 6,911,217; U.S. Pat. No. 5,164,190; U.S. Pat. No. 5,601,839;U.S. Pat. No. 5,834,010; U.S. Pat. No. 6,743,441; WO2002000652;WO200400414853. These also include trospium chloride, darifenacin andimidafenacin (KRP-197). As will be appreciate by those of skill in theart, these drugs may be administered orally or topically in standard orextended release forms, such as extended release tolterodine, extendedrelease oxybutynin and transdermal oxybutynin.

Within the aspect of the invention discussed above, there is a genuswherein the anti-muscarinic agent is selected from tolterodine,oxybutynin, trospium, vamicamide, solifenacin, propiverine,S-oxybutynin, temiverine, sanctura, staybla, fesoterodine, SVT40776,202405 by GlaxoSmithKline, TD6301, RBX9841, DDP200, and PLD179.

Within the aspect of the invention discussed above, there is a genuswherein the anti-muscarinic agent is selected from the group consistingof trospium chloride, darifenacin and imidafenacin.

Within the aspect of the invention discussed above, there is a genuswherein the anti-muscarinic agent is selected from the group consistingof extended release tolterodine, extended release oxybutynin andtransdermal oxybutynin.

For purposes of this specification the 5-alpha reductase inhibitorincludes, but is not limited to finasteride, dutasteride, turosterideand epristeride.

By the term “finasteride” as used here is meant the compound asdesignated by 4-azaandrost-1-ene-17-carboxamide,N-(1,1-dimethylethyl)-3-oxo-,(5α,17β). FDA approved doses forfinasteride are 1 mg and 5 mg, once a day.

By the term “dutasteride” as used herein is meant the compound asdesignated by(5α,17β)-N-{2,5bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide.FDA approved doses for finasteride are 1 mg and 5 mg, once a day. TheFDA approved dose for dutasteride is 0.5 mg, once a day. The FDAapproved dose for dutasteride is 0.5 mg, once a day.

For purposes of this specification the alpha-adrenergic receptorantagonist is selected from amsulosin, terazosin, doxazosin, alfuzosin,indoramin and prazosin.

By the term “amsulosin” (e.g. Flomax or tamsulosin hydrochloride) asused herein is meant the compound designated as(−)-(R)-5-[2-[[2-(O-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamideand salts, hydrates and solvates thereof. Amsulosin is disclosed in U.S.Pat. No. 4,703,063 and claimed in U.S. Pat. No. 4,987,152 as beinguseful in treating lower urinary tract dysfunction. FDA approved dosesinclude 0.4 mg once a day for tamsulosin hydrochloride.

By the term “terazosin” as used herein is meant the compound1-(4-amino-6,7-dimethoxy-2quinazolinyl)-4-[(tetrahydro-2-furoyl)carbonyl]piperazineand salts, hydrates and solvates thereof. Terazosin is disclosed in U.S.Pat. No. 4,251,532. FDA approved doses include 1, 2, 5 and 10 mg once aday for terazosin hydrochloride.

By the term doxazosin as used herein is meant the compoundI-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]-piperazineand salts, hydrates and solvates thereof. Doxazosin is disclosed in U.S.Pat. No. 4,188,390. FDA approved doses include 1, 2, 4 and 8 mg once aday for doxazosin mesylate.

By the term “alfuzosin” (e.g. Uroxatral) as used herein is meant thecompoundN-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamideand salts, hydrates and solvates thereof. Alfuzosin is disclosed in U.S.Pat. No. 4,315,007. FDA approved doses include 10 mg once a day foralfuzosin hydrochloride.

By the term “indoramin” as used herein is meant the compoundN-[[1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl]benzamine. Indoramin isdisclosed in U.S. Pat. No. 3,527,761.

By the term “prazosin” as used herein is meant a compound of the formula1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine.and solvates thereof. Prazosin is disclosed in U.S. Pat. No. 3,511,836.FDA approved doses include 1, 2 and 5 mg once a day for prazosinhydrochloride.)

It will be appreciated that when using any combination described herein,both the compound of the present invention and the other active agent(s)will be administered to a patient, within a reasonable period of time.The compounds may be in the same pharmaceutically acceptable carrier andtherefore administered simultaneously. They may be in separatepharmaceutical carriers such as conventional oral dosage forms which aretaken simultaneously. The term “combination” also refers to the casewhere the compounds are provided in separate dosage forms and areadministered sequentially. Therefore, by way of example, one activecomponent may be administered as a tablet and then, within a reasonableperiod of time, the second active component may be administered eitheras an oral dosage form such as a tablet or a fast-dissolving oral dosageform. By a “fast dissolving oral formulation” is meant, an oral deliveryform which when placed on the tongue of a patient, dissolves withinabout 10 seconds.

By “reasonable period of time” is meant a time period that is not inexcess of about 1 hour. That is, for example, if the first activecomponent is provided as a tablet, then within one hour, the secondactive component should be administered, either in the same type ofdosage form, or another dosage form which provides effective delivery ofthe medicament.

The compounds of this invention may be administered to patients (animalsand humans) in need of such treatment in dosages that will provideoptimal pharmaceutical efficacy. It will be appreciated that the doserequired for use in any particular application will vary from patient topatient, not only with the particular compound or composition selected,but also with the route of administration, the nature of the conditionbeing treated, the age and condition of the patient, concurrentmedication or special diets then being followed by the patient, andother factors which those skilled in the art will recognize, with theappropriate dosage ultimately being at the discretion of the attendantphysician.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level of the compounds of the presentinvention, or pharmaceutically acceptable salts thereof, is about 0.001to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such asfrom about 0.05 to about 10 mg/kg per day. The dosage range willgenerally be about 0.5 to 1000 mg per patient per day, which may beadministered in single or multiple doses. Preferably, the dosage rangewill be about 0.5 mg to 500 mg per patient per day; more preferablyabout 0.5 mg to 200 mg per patient per day; and even more preferablyabout 5 mg to 50 mg per patient per day. Specific dosages of thecompounds of the present invention, or pharmaceutically acceptable saltsthereof, for administration include 1 mg, 5 mg, 10 mg, 30 mg, 100 mg,and 500 mg.

Pharmaceutical compositions of the present invention may be provided ina formulation comprising about 0.5 mg to 1000 mg active ingredient; morepreferably comprising about 0.5 mg to 500 mg active ingredient; or 0.5mg to 250 mg active ingredient; or 1 mg to 100 mg active ingredient.Specific pharmaceutical compositions for treatment or prevention ofexcess tachykinins comprise about 1 mg, 5 mg, 10 mg, 30 mg, 100 mg, and500 mg of active ingredient.

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Starting materials and therequisite intermediates are in some cases commercially available, or canbe prepared according to literature procedures or as illustrated herein.All NMR spectra were obtained on instrumentation at field strength of400 or 500 MHz.

Example 1

tert-Butyl(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylateand tert-butyl(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate(mixture of two isomers) Step A:N-Methoxy-N-methyl-2-(2-methylphenyl)acetamide

To a solution of (2-methylphenyl)acetic acid in dry methylene chloride(16.7 g, 108.4 mmol) under nitrogen atmosphere was addedN,O-dimethylhydroxylamine (13.8 g, 141.5 mmol), triethylamine (20 mL,143.8 mmol), 4-dimethylaminopyridine (DMAP, 14.2 g, 119.3 mmol) and EDC(27 g, 140.6 mmol). The reaction mixture was stirred at RT for 2 hr thentransferred to a separation funnel. The mixture was washed consecutivelywith 2 N aq. HCl, brine, saturated aq. NaHCO₃ and brine. The organiclayer was dried over MgSO₄, filtered and the solvent evaporated undervacuum to give 21 g of the crude title compound which was used withoutfurther purification. ¹H-NMR (CDCl₃): δ: 7.20 (4H, m), 3.80 (2H, s),3.65 (2H, s), 3.65 (3H, s), 2.34 (3H, m).

Step B: 1-(2-Methylphenyl)but-3-en-2-one

To a solution of vinylmagnesium bromide (220 mL, 1.0 M, 220 mmol) in 100mL THF, was added dropwise under nitrogen atmosphere at 0° C. a solutionof 2-(2-methylphenyl)-N-methoxy-N-methylacetamide (Step A, 21 g, 106.6mmol) in ˜150 mL dry ether. The reaction mixture was stirred at 0° C.for 0.5 hr then poured slowly into an ice/2N aq HCl (300 mL) mixture.The resulting mixture was diluted with ether, transferred to aseparation funnel. The organic layer was separated, washed with brine,dried over MgSO₄, filtered and the solvent evaporated under vacuum togive 14.2 g of the crude title compound which was used without furtherpurification. ¹H-NMR (CDCl₃): δ: 7.15-7.25 (4H, m), 6.47 (1H, dd,J₁=14.2 Hz, J₂=11 Hz), 6.35 (1H, d, J=14.2 Hz), 5.86 (1H, d, J=11 Hz),3.83 (2H, s), 2.28 (3H, s).

Step C: Triethyl {[(1Z)-1-(2-methylbenzylidene)prop-2-en-1-yl]oxy}silaneand triethyl {[(1E)-1-(2-methylbenzylidene)prop-2-en-1-yl]oxy}silane

To a solution of 1-(2-methylphenyl)but-3-en-2-one (Step B, 14.2 g, 86.6mmol, 1 equiv.) and diisopropylethylamine (24.1 mL, 138.6 mmol, 1. 6equiv.) in a mixture of solvents of acetonitrile, THF and toluene (200mL:100 mL:25 mL) was added chlorotriethylsilane (23.4 mL, 1.6 equiv.138.6 mmol) via a separation funnel at room temperature. The resultingsolution was allowed to stir overnight at room temperature. The reactionmixture was quenched with 185 mL 2% ammonium chloride (4 g). The organiclayer was separated and washed with 185 mL water, dried over anhydrousMgSO4 and concentrated under vacuum to give 20.5 g of the crude titlecompounds which were used without further purification. ¹H-NMR (CDCl₃):δ: 7.68 (1H, d, J=7.8 Hz), 7.15 (3H, m), 6.32 (1H, dd, J₁=13.2 Hz,J₂=8.5 Hz), 5.82 (1H, s), 5.55 (1H, d, J=13.2 Hz), 5.18 (1H, d, J=8.5Hz).

Step D: Diethyl(1S,2S)-3-(2-methylphenyl)-4-[(triethylsilyl)oxy]cyclohex-4-ene-1,2-dicarboxylate,diethyl(1R,2R)-3-(2-methylphenyl)-4-[(triethylsilyl)oxy]cyclohex-4-ene-1,2-dicarboxylate,diethyl(1S,2R)-3-(2-methylphenyl)-4-[(triethylsilyl)oxy]cyclohex-3-ene-1,2-dicarboxylateand diethyl(1R,2S)-3-(2-methylphenyl)-4-[(triethylsilyl)oxy]cyclohex-3-ene-1,2-dicarboxylate

To a solution of 1E and1Z-{[1-(2-methylbenzylidene)prop-2-en-1-yl]oxy}triethylsilanes (Step C,14 g, ˜80% pure, 133.1 mmol, 1 equiv.) and diethyl (2E)-but-2-enedioate(6.5 mL, 6.85 g, 39.6 mmol) in 100 mL xylenes under nitrogen atmospherewas heated at 160° C. for 5 hr then cooled to RT. The solvent wasevaporated under vacuum to give an oil which was used without furtherpurification.

Step E: Racemic diethyl(1S,2S,3R)-3-(2-methylphenyl)-4-oxocyclohexane-1,2-dicarboxylate anddiethyl (1R,2R,3S)-3-(2-methylphenyl)-4-oxocyclohexane-1,2-dicarboxylate

To a solution of the above intermediate (Step D) in acetonitrile (150mL) was added hydrochloric acid (6 N, 10 mL). The resulting mixture wasstirred at RT for 24 hr, and the volatiles were removed under vacuum.The crude oil was dissolved in 200 mL ethyl acetate, and the solutionwas washed with brine, dried over anhydrous magnesium sulfate. Themagnesium salt was filtered off and the solvent was evaporated undervacuum to give 18.2 g of the title compounds which were purified bycolumn chromatograph (5:1 hexane:ethyl acetate). ¹H-NMR (CDCl₃): δ: 7.32(1H, d, J=7.8 Hz), 7.25 (1H, m), 7.14 (2H, m), 4.15 (2H, m), 3.85-3.70(3H, m), 3.13 (1H, t, J=12.9 Hz), 2.85 (2H, m), 2.33 (3H, s), 2.15 (2H,m), 1.58-1.72 (2H, m), 1.26 (3H, t, J=7.2 Hz), 0.75 (3H, t, J=7.2 Hz).

Step F: Racemic diethyl(1S,2S,3R,4S)-4-hydroxy-3-(2-methylphenyl)cyclohexane-1,2-dicarboxylateand diethyl(1R,2R,3S,4R)-4-hydroxy-3-(2-methylphenyl)cyclohexane-1,2-dicarboxylate

To a solution of lithium tri-tertial-butoxyaluminum hydride (66 mL, 1 M,66 mmol) in 150 mL THF was added a solution of the intermediate of stepE (15.2 g, 45.1 mmol) in 75 mL THF under nitrogen atmosphere at −40° C.was added via syringe. The resulting mixture was stirred at −40° C. for2 hr then at RT for 2 hr. The reaction mixture was carefully quenched byaddition of 15 mL water and 30 mL 2 N hydrochloric acid. The emulsionwas diluted with ethyl acetate and the mixture was stirred for 1 hr. Thesolid was then filtered through celite. The filtrate was dried (MgSO₄)and the solvent evaporated under vacuum to give the crude titlecompounds which were purified by column chromatography to afford 13 gsolid. ¹H-NMR (CDCl₃): δ: 7.32 (1H, d, J=9.6 Hz), 7.25 (1H, m), 7.14(2H, m)), 4.13 (2H, m), 3.87-3.65 (2H, m), 3.14 (1H, t, J=10.3 Hz), 2.86(2H, m), 2.35 (3H, s), 2.25 (2H, m), 1.78-1.58 (2H, m), 1.23 (3H, t,J=7.1 Hz).

Step G: Diethyl(1S,2S,3R,4S)-4-hydroxy-3-(2-methylphenyl)cyclohexane-1,2-dicarboxylate

13 g of the racemic mixture of diethyl(1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylateand diethyl(1R,2R,3S,4R)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate(step F) was separated by preparative chiral HPLC using CHIRACEL ADcolumn eluting with hexanes/i-PrOH (9/1) to afford 6 g of the desiredfirst eluting isomer diethyl(1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate.

Step H:(1S,2R,3R,4S)-3,4-Bis(hydroxymethyl)-2-(2-methylphenyl)cyclohexanol

To a solution of diethyl(1S,2S,3R,4S)-4-hydroxy-3-(2-methylphenyl)cyclohexane-1,2-dicarboxylate(Step G, 64.1 g, 192 mmol) in 250 mL THF under nitrogen atmosphere wasslowly added LiBH₄ powder (16.7 g, 767 mmol, excess) at 0° C. Theresulting mixture was heated at 75° C. for 12 hr then cooled to RT. Thereaction mixture was carefully quenched by addition of 30 mL water at 0°C., then 30 mL 2 N hydrochloric acid. The organic layer was separatedand the aqueous was extracted with EtOAc. The combined organic extractswere washed with aqueous NaHCO₃, dried over Na₂SO₄, filtered and thesolvent evaporated under vacuum to give 43.7 g of the crude titlecompound which was used without further purification. ¹H-NMR (CDCl₃): δ:7.30-7.13 (4H, m), 3.93-3.68 (3H, m), 3.53 (1H, dd, J₁=11.2 Hz, J₂=2.3Hz), 3.27 (1H, dd, J₁=11.2 Hz, J₂=5.1 Hz), 2.85 (1H, t, J=10.5 Hz), 2.39(3H, s), 2.19 (1H, m), 1.86 (3H, bs), 1.67 (2H, m), 1.55 (1H, m), 1.45(1H, m).

Step I:[(1S,2R,3R,4S)-4-Hydroxy-3-(2-methylphenyl)cyclohexane-1,2-diyl]bis(methylene)dipropane-1-sulfonate

To a solution of(1S,2R,3R,4S)-3,4-Bis(hydroxymethyl)-2-(2-methylphenyl)cyclohexanol(Step H, 43.7 g, 175 mmol) in 100 mL methylene chloride and 100 mLacetonitrile was added propanesulfonyl chloride (44.9 mL, 402 mmol) and2,6-lutidine (61.0 mL, 524 mmol) at room temperature. The reactionmixture was stirred at room temperature for 24 hr and was monitored byLC-MS (M⁺+23=485 for bis-sulfonate and M⁺+23=379 for monosulfonate).LC-MS showed some mono-sulfonate. 0.5 equivalent of n-propanesulfonylchloride (9.8 mL, 88 mmol) and 0.6 equivalent of 2,6-lutidine (12.2 mL,104.8 mmol) were added. The resultant mixture was stirred for 17 hr. Thereaction was quenched with 2 N HCl aqueous and diluted with ether. Theorganic layer was separated, and was washed with brine. The aqueous wasextracted with ether. The combined organic extract was washed withbrine, dried over MgSO4. The dry agent was removed by filtration, andthe filtrate was concentrated to give an oil, which was used withoutfurther purification. M⁺+23: 485.34.

Step J:(3aR,4R,5S,7aS)-2-benzyl-4-(2-methylphenyl)octahydro-1H-isoindol-5-ol

In a pressure tube was placed a solution of crude[(1S,2R,3R,4S)-4-hydroxy-3-(2-methylphenyl)cyclohexane-1,2-diyl]di(methylene)dipropanesulfonate (Step 1.85 g, 184 mmol) in ˜120 mL ethanol andbenzylamine (70.2 mL, 643 mmol). The pressure tube was sealed and heatedat 140° C. in an oil bath for 3 hr. The tube was cooled to RT andopened. LC-MS showed that the reaction was completed. The resultingmixture was diluted with 180 mL methanol and 100 mL 5 N aq. NaOH. Theethanol, some of water and benzylamine were removed under vacuum. Theresidue was dissolved in ethyl acetate and diluted with water. Theorganic layer was separated and the aqueous was extracted with ethylacetate. The combined organic layers were dried over MgSO₄, filtered andthe solvent was evaporated under vacuum. The combined organics wereconcentrated, and the residue oil was purified by column chromatography(1:9 methanol:ethyl acetate. ¹H-NMR (CDCl₃): δ: 7.35-7.10 (9H, m),3.81-3.62 (3H, m), 2.94 (1H, t, J=8.1 Hz), 2.83 (1H, t, J=10.0 Hz), 2.52(2H, m), 2.40 (1H, t, J=10.0 Hz), 2.36 (3H, s), 2.20 (1H, m), 2.02-1.85(3H, m), 1.60 (1H, m), 1.36 (1H, m). M⁺+1: 322.19.

Step K: tert-Butyl(3aR,4R,5S,7aS)-5-hydroxy-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate

To a solution of(3aR,4R,5S,7aS)-2-benzyl-5-hydroxy-4-(2-methylphenyl)octahydro-1H-isoindole(Step J, 43.5 g) in 150 mL EtOH was added Pd(OH)₂—C (14.25 g, 20.3 mmol,20% by weight). The reaction mixture was hydrogenated at 50 PSI for 16hr at RT. The catalyst was filtered, and the solvent of the filtrate wasevaporated under vacuum to give the title compound (31.0 g) which wasdirectly used in the next step without purification. M⁺+1: 232.30. Thehydroisoindoline (31 g, 134 mmol) was dissolved in methylene chloride(300 mL), and the solution was stirred with di(t-butyl)bicarbonate (43.9g, 201 mmol) at room temperature overnight. The solvent was removed andthe crude material was purified by silica gel column chromatography (2:1hexane:ethyl acetate) to give 34.0 g of the desired compound. ¹H-NMR(CDCl₃): δ: 7.32-7.11 (4H, m), 3.90-3.73 (1H, m), 3.68, 3.60 (1H, twomultiplets), 3.25, 3.15 (1H, two multiplets), 2.96, 2.72 (4H, twomultiplets), 2.41, 2.37 (3H, two singlets), 2.26 (1H, m), 2.11-1.80 (3H,m), 1.62 (1H, m), 1.62 (3H, s), 1.45, 1.42 (6H, two singlets).M⁺+1−57+1: 276.11.

Step L: 4-Methylbenzenesulfonyl azide

A solution d sodium azide (3.19 g, 44.6 mmol) in 15 mL water is placedin a 250 mL Erlenmeyer flask and was diluted with 40 mL 90% aqueousethanol. To this solution was added with stirring a warm (45° C.)solution of 4-methanesulfonyl chloride (8.5 g, 44.6 mL) in 40 mLethanol. After the mixture was stirred at room temperature for 2.5 hr,most of the solvent was removed under vacuum at 35° C. The residue wasdissolved in ethyl acetate and water, and was transferred into aseparation funnel. The organic layer was separated, washed with brine,dried over MgSO4 and the solvent was removed (8.0 g). ¹H-NMR (CDCl₃): δ:7.86 (2H, d, J=8.2 Hz), 7.41 (2H, d, J=8.3 Hz), 2.46 (3H, s).

Step M: Ethyl 3,5-bis(trifluoromethyl)phenylacetate

To a solution of 3,5-bis(trifluoromethyl)phenylacetic acid (24.65 g, 91mmol) in dichloromethane (150 mL), was added 200 proof ethanol (10.63mL, 181 mmol), EDC (34.7 g, 181 mmol) and 4-(N,N-dimethylaminopyridine(DMAP, 14.39 g, 118 mmol) at room temperature. The solution was stirredat RT over night, washed with 2 N HCl and saturated aqueous sodiumbicarbonate. The organic layer was dried over MgSO4, and the solvent wasremoved under vacuum to provide 26 g (96%) of the title compound.

Step N: Ethyl [3,5-bis(trifluoromethyl)phenyl](diazo)acetate

To a solution of ethyl 3,5-bis(trifluoromethyl)phenylacetate (Step M,26.0 g, 87 mmol) and 4-methylbenzenesulfonyl azide (Step L, 18.0 g, 91mmol) in dry acetonitrile (150 mL) was added DBU (14.3 mL, 95 mmol)dropwise at −10° C. over 15 min with stirring. The mixture was stirredat −10° C. for a further 0.5 hr. The solvent was removed and the residuewas partitioned between ether and water. The organic layer was washedwith aqueous NaHCO₃, brine, dried over Mg₂SO₄, and the solvent wasremoved. The residue was chromatographed (eluted with 9:1 hexane:ethylacetate) to afforded a yellow solid. ¹H-NMR (CDCl₃): δ: 8.0 (2H, s),7.68 (1H, s), 4.41 (2H, d, J=7.1 Hz), 1.40 (3H, t, J=7.1 Hz).

Step O: tert-Butyl(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-ethoxy-2-oxoethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylateand tert-butyl(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-2-ethoxy-2-oxoethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate

To a solution of the alcohol intermediate of Step K (34 g, 105 mmol) inbenzene (150 mL) at 85° C. in the presence of rhodium acetate (0.1equiv., 2.32 g, 10.26 mmol) was added by slow addition over 8 hrs. bysyringe pump, a solution of the diazoester (intermediate Step N, 45.7 g,123 mmol) in benzene (80 mL). After completion of the reaction, solventwas removed under vacuum and the residue was purified by columnchromatography (4:1 hexane:ethyl acetate) to give a product mixture oftwo components (45 g). M⁺+1−57+1: 574.20.

Step P: tert-Butyl(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylateand tert-butyl(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate

To a solution of 2.2 g (3.57 mmol) of tert-butyl(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-1-(ethoxycarbonyl)methoxy}-4-(2-methylphenyl)octahydro-1H-isoindole-2-carboxylateand tert-butyl(3aS,4S,5R,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-1-(ethoxycarbonyl)}methoxy-4-(2-methylphenyl)octahydro-1H-isoindole-2-carboxylate(intermediates Step O) in 50 mL THF under nitrogen atmosphere was addedLiBH₄ powder (0.16 g, 7.15 mmol) at 0° C. The resulting mixture washeated at 75° C. for 3 hr then cooled to RT. The reaction mixture wascarefully quenched by the addition of 30 mL water at 0° C. and 30 mLsaturated aqueous KHSO₄, then extracted with ethyl acetate. The combinedorganic extracts were dried over MgSO₄, filtered and the solventevaporated under vacuum. The crude compounds were separated by columnchromatography (eluted with 2:1 hexane:EtOAc, then 1:1 hexane:EtOAc) toafford the title compounds. The more polar isomer by TLC was assigned(15) isomer (1.1 g). M⁺+1−57+1: 532.36. The less polar component on TLCwas assigned as the (1R) structure.

Example 2

(2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-4-(2-methylphenyl)octahydro-1H-isoindol-5-yl]oxy}ethanol

The more polar isomer (1S) isomer of EXAMPLE 1 (tert-butyl(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate,2.0 g, 3.4 mmol) was stirred in 4 N HCl in dioxane for 1 hr. Thevolatiles were removed, and the residue was taken into ethyl acetate.The organic layer was separated, and the aqueous was extracted withethyl acetate. The combined organic layers were washed consecutivelywith 2 N NaOH, brine, dried over MgSO₄ and the solvent was removed togive 1.65 g of the amine title compound. M⁺+1: 488.22

Example 3

3-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one

To a solution of(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(tri-fluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)octahydro-1H-isoindole(1.65 g, 3.38 mmol, EXAMPLE 2) in 10 mL methanol was added 1 mL aceticacid. The volatiles were removed under vacuum and the residue wasdissolved in 50 mL 2-propanol. The solution was heated withcyclopentadione (1.33 g, 13.54 mmol) at 80° C. overnight. The solventwas removed and the residue was taken into ethyl acetate. The solutionwas washed with 2 N aqueous sodium hydroxide and brine. The organiclayer was dried over MgSO₄, and the solvent was removed. The residue waspurified by column chromatography (9:1 ethyl acetate:methanol) to give1.2 g of the title compound. ¹H-NMR (CDCl₃): δ: 7.69 (1H, s), 7.16 (2H,s), 7.08-6.90 (4H, m), 4.87, 4.68 (1H, two singlets), 4.42 (1H, m),3.70, 3.57-3.47 (3H, m), 3.17 (0.65H, m), 3.08 (0.35H, t, J=10.1 Hz),2.98 (2H, m), 2.90 (0.65H, t, J=10.1 Hz), 2.77 (0.35H, t, J=10.1 Hz),2.59-2.48 (2H, m), 2.42-2.33 (3H, m), 2.30 (3H, s), 2.17 (1H, m), 2.00(2H, m), 1.65 (1H, m), 1.40 (1H, m). M⁺+1: 568.23.

Example 4

3-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-methoxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one

The compound from EXAMPLE 3 (0.02 g, 0.035 mmol) was dissolved in DMF(15 mL) and cooled to 0° C. NaH solid (12.8 mg, 0.07 mmol) was added,and the reaction mixture was stirred at 0° C. for 5 min. A few drops ofiodomethane (excess) were added to the mixture. After stirring foranother 10 min at 0° C., water (1 mL) was added and the water/DMF wereremoved in vacuo. The residue was taken into ethyl acetate. The mixturewas washed with water, dried over magnesium sulfate and concentrated.The crude material was purified by preparative TLC (10% methanol inethyl acetate) to afford the title compound. M⁺+1: 582.47.

Example 5

2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-oneStep A: tert-butyl(3aR,4R,5S,7aS)-5-{(1S)-2-(benzoyloxy)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate

To a solution of the (1S) isomer of EXAMPLE 1 (tert-Butyl(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate,8.61 g, 14.65 mmol) in 50 mL pyridine was added benzoyl chloride (3.40mL, 29.3 mmol). The mixture was stirred at 50° C. for 16 hr. Thevolatiles were removed in vacuo. The residue was dissolved in 200 mLethyl acetate, washed with sodium bicarbonate aqueous and brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by column chromatography (EtOAc/hexane, 15% to 30%for 2900 mL, then 30% to 50% for 1250 mL) to give 10.38 g (102% yield)of the title compound. M⁺+1: 588.1.

Step B:(2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-4-(2-methylphenyl)octahydro-1H-isoindol-5-yl]oxy}ethylbenzoate

The intermediate from step A (8.6 g, 12.43 mmol) was added to 4 N HCl indioxane (200 mL) at 0° C. The solution was then stirred at roomtemperature for 1 h. The volatiles were removed in vacuo. The residuewas dissolved in 750 mL ether, washed with 2N sodium hydroxide aqueous,brine and saturated sodium bicarbonate. The organic layer was dried overNa₂SO₄ and concentrated in vacuo to give a foam solid (8.12 g crude).M⁺+1: 592.49.

Step C:(2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-2-{[(chloroacetyl)amino]carbonyl}-4-(2-methylphenyl)octahydro-1H-isoindol-5-yl]oxy}ethylbenzoate

To a solution of the intermediate from Step B (7.35 g, 12.43 mmol) in150 mL methylene chloride was added N-(chloroloaceto)isocyanate at 0° C.The solution was stirred at rt for 1 hr, and was diluted with methylenechloride. The organic layer was separated and the aqueous layer wasextracted with methylene chloride. The combined organic layers werewashed with aqueous sodium bicarbonate, dried over Na₂SO₄ and thesolvent was removed under vacuum. The off-white solid was directly usedin the next step. M⁺+1=711.1.

Step D:(2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-4-(2-methylphenyl)-2-(4-oxo-4,5-dihydro-1,3-oxazol-2-yl)octahydro-1H-isoindol-5-yl]oxy}ethylbenzoate

A solution of the intermediate from Step C (8.84 g, 12.43 mmol) in THF(600 mL) and DBU (3.75 mL, 24.86 mmol) was heated at 50° C. for 2.5 hr.The volatiles were removed, and the crude material was purified bycolumn chromatography [(6% methanol/EtOAc)/EtOAC 0 to 66% for 2900 mL,then 66% to 80% for 1200 mL] to give the title compound. M⁺+1: 613.60.

Step E:2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one

To a solution of benzoate of Step D (4.0 g, 5.93 mmol) in 200 mL ofmethanol was added 6.0 mL of 2 M sodium hydroxide. The reaction mixturewas maintained at ambient temperature for 1 hr, and diluted with 1200 mLether. The organic layer was washed with 1 M sodium hydroxide (400 mL).The organic layer was then washed with water, dried over MgSO₄,filtered, and concentrated to afford a white solid. The crude materialwas purified by flash chromatography (0-5% then 5-7% them 7% methanol inethyl acetate. M++1: 571.2.

Example 6

(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-N,N-dimethyl-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxamideStep A: tert-Butyl(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-(acetohydroxyethoxy)}-4-(2-methylphenyl)octahydro-1H-isoindole-2-t-butylcarboxylate

To a solution of the (1S) isomer of EXAMPLE 1 ((tert-Butyl(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate,1.3 g, 2.2 mmol) in methylene chloride (45 mL) was added acetyl chloride(0.26 mL, 3.32 mmol), TEA (0.93 mL, 6.64 mmol) and a catalytical amountof 4-(N,N-dimethyl)pyridine (DMAP, 0.02 g) at 0° C. The mixture wasstirred at the same temperature for 1 hr. TLC showed the startingmaterial disappeared. The reaction mixture was diluted with methylenechloride, washed with aqueous KHSO₄, brine, aqueous NaHCO₃, dried overMgSO₄ and the solvent was removed. The crude material was purified withby preparative TLC (1.1 g), M⁺+1−57+1: 574.00.

Step B:(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-(acetohydroxyethoxy)}-4-(2-methylphenyl)octahydro-1H-isoindole

The above compound (Step A, 1.1 g, mmol) in 15 mL 4 N HCl in dioxane wasstirred for 1 hr. The volatiles were removed under vacuum in 40° C.water bath. The residue was dissolved in ethyl acetate. The solution waswashed with NaHCO₃ aqueous, brine, dried over MgSO₄, and the solvent wasremoved to give 0.85 g. The compound was kept in freezer. M⁺+1: 532.02.

Step C:(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-N,N-dimethyl-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxamide

To a solution of the above compound (Step B, 0.13 g, 0.25 mmol) in 25 mLmethylene chloride were added N,N-dimethyl chloroformide (0.03 mL, 0.33mmol), triethyl amine (0.055 mL, 0.040 mmol) and a catalytical amount ofDMAP at room temperature. The mixture was stirred at the sametemperature for 1 hr. The solvent was removed and the residue was heatedwith 10 mL 2 N NaOH in 40 mL methanol at 50° C. for 1 hr. Methanol wasremoved under vacuum. The residue was diluted with water, and theaqueous was extracted with ethyl acetate. The organic layers were washedwith brine, dried (MgSO4) and the solvent was removed. The residue waspurified by preparative TLC (95:5 EtOAc:methanol), 0.07 mg. M⁺+1:559.04.

Example 7

(2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-2-isobutyryl-4-(2-methylphenyl)octahydro-1H-isoindol-5-yl]oxy}ethanol

To a solution of the compound from EXAMPLE 2 in CH₂Cl₂ was addedisobutyric chloride, triethylamine and a catalytic amount of DMAP. Themixture was stirred at room temperature for 2 hr. The solvent wasremoved and the residue was heated with 10 mL 2 N NaOH in 40 mL methanolat 50° C. for 1 hr. Methanol was removed under vacuum. The residue wasdiluted with water and the aqueous was extracted with ethyl acetate. Theorganic layer was washed with brine, dried (MgSO₄) and the solvent wasremoved. The residue was purified by preparative TLC (80:20EtOAc:hexane), 0.07 mg. M++1: 558.16.

Using the procedures essentially comparable to those described above thecompounds of the following Examples were prepared.

parent ion Ex. # R¹ X Y Z (MH⁺) m/z 8

F H H 575.4 9

F H H 572.2 10

F CH₃ H 589.6 11

F CH₃ H 586.1 12

H CH₃ H 572.4 13

H CH₃ H 556.2 14

H CH₃ CH₃ 573.4 15

F H H 536.3 (M⁺ + 1 − 56) 16 H F H H 492.2 17 H H CH₃ C₆H₅CO 592.4 18

H CH₃ CH₃CO 613.3 19

H CH₃ C₆H₅CO 675.4 20

H CH₃ C₆H₅CO 636.5 (M⁺ + 1 − 56)

parent ion Ex. # R¹ X Y Z (MH⁺) m/z 21

F H H 572.3 22 H H CH₃ H 488.2 23

H CH₃ H 568.2 24

H CH₃ H 572.4 25

H CH₃ H 559.0 26

F H H 536.3 (M⁺ + 1 − 56) 27 H F H H 492.2

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above.

1. A compound of the formula I:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof wherein: R¹ is selected from the groupconsisting of: (1) hydrogen, (2) C₁₋₆alkyl, which is unsubstituted orsubstituted with halogen, hydroxyl or phenyl, (3) cyclopentenone, whichis unsubstituted or substituted with hydroxyl, (4) —(CO)—C₁₋₆alkyl, (5)—(CO)—NH₂, (6) —(CO)—NHC₁₋₆alkyl, (7) —(CO)—N(C₁₋₆alkyl)(C₁₋₆alkyl), (8)—(CO)—O—C₁₋₆alkyl, (9) —(CO)—C₃₋₆cycloalkyl, and

X is independently selected from the group consisting of: (1) hydrogen,and (2) fluorine; Y is independently selected from the group consistingof: (1) hydrogen, and (2) methyl; Z is independently selected from thegroup consisting of: (1) hydrogen, (2) C₁₋₆alkyl, which is unsubstitutedor substituted with halogen, hydroxyl or phenyl, (3) —(CO)—C₁₋₆alkyl,(4) —(CO)-Aryl (5) —(CO)O—C₁₋₆alkyl, (6) —(CO)—NH₂, (7)—(CO)—NHC₁₋₆alkyl, and (8) —(CO)—N(C₁₋₆alkyl)(C₁₋₆alkyl), wherein thealkyl portion of choices (4), (7) and (8) of R¹ are optionallysubstituted with halo, hydroxyl or phenyl.
 2. The compound of claim 1 ofthe formula Ia or Ib:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof.
 3. The compound of claim 2 of the formula Ia:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof.
 4. The compound of claim 2 of the formula Ib:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof.
 5. The compound of claim 1 wherein R¹ isselected from the group consisting of: (1) hydrogen, (2) C₁₋₃alkyl,which is unsubstituted or substituted with hydroxyl or phenyl, (3)cyclopent-2-en-1-one, which is unsubstituted or substituted withhydroxyl, (4) —(CO)—C₁₋₃alkyl, (5) —(CO)—NH₂, (6) —(CO)—NHC₁₋₃alkyl, (7)—(CO)—N(C₁₋₃alkyl)(C₁₋₃alkyl), and

wherein the alkyl portion of choices (4), (6) and (7) of R¹ areoptionally substituted with halo, hydroxyl or phenyl.
 6. The compound ofclaim 1 wherein R¹ is selected from the group consisting of: (1)hydrogen, (2) cyclopent-2-en-1-one, (3) 1,2-oxazol-4(5H)-one, (4)2,2-dimethylpropanoyl, (5) methylpropanoyl, (6) CH₃NH—(CO)—, (7)(CH3)2-N—(CO)—, and


7. The compound of claim 1 wherein Z is selected from the groupconsisting of (1) hydrogen, (2) C₁₋₃alkyl, which is unsubstituted orsubstituted with halogen, hydroxyl or phenyl, (3) —(CO)-phenyl, and (4)—(CO)O-methyl.
 8. The compound of claim 1 wherein X is hydrogen.
 9. Thecompound of claim 1 wherein X is fluorine.
 10. The compound of claim 1wherein Y is hydrogen.
 11. The compound of claim 1 wherein Y is methyl.12. The compound of claim 1 wherein Z is hydrogen.
 13. The compound ofclaim 1 wherein Z is methyl.
 14. The compound of claim 1 of the formulaIa or Ib:

or a pharmaceutically acceptable salt thereof and individual enantiomersand diastereomers thereof wherein R¹ is selected from the groupconsisting of: (1) hydrogen, (2) cyclopent-2-en-1-one, (3)1,2-oxazol-4(5H)-one, (4) 2,2-dimethylpropanoyl, (5) methylpropanoyl,(6) CH₃NH—(CO)—, (7) (CH₃)₂—N—(CO)—, and

X is independently selected from the group consisting of: (1) hydrogen,and (2) fluorine; Y is independently selected from the group consistingof: (1) hydrogen, and (2) methyl; Z is independently selected from thegroup consisting of: (1) hydrogen, (2) C₁₋₆alkyl, which is unsubstitutedor substituted with halogen, hydroxyl or phenyl, (3) —(CO)—C₁₋₆alkyl,(4) —(CO)-Aryl (5) —(CO)O—C₁₋₆alkyl, (6) —(CO)—NH₂, (7)—(CO)—NHC₁₋₆alkyl, and (8) —(CO)—N(C₁₋₆alkyl)(C₁₋₆alkyl).
 15. A compoundof claim 14 wherein Z is selected from the group consisting of (1)hydrogen, (2) C₁₋₃alkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl, (3) —(CO)-phenyl, and (4) —(CO)O-methyl.16. A compound of claim 14 wherein Z is selected from hydrogen andmethyl.
 17. A compound which is selected from the group consisting of:

and pharmaceutically acceptable salts thereof
 18. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1.19. A method for the treatment of pain or inflammation, migraine,emesis, post-therapeutic neuralgia, depression, anxiety or urinaryincontinence, and LUTS which method comprises administration to apatient in need thereof a therapeutically effective amount of thecompound of claim
 1. 20. A method according to claim 19 for thetreatment of urinary incontinence or LUTS.
 21. A method of antagonizingthe effect of substance P at its receptor site or for the blockade ofneurokinin-1 receptors in a patient in need thereof comprisingadministration to said patient a therapeutically effective amount of thecompound of claim
 1. 22. (canceled)
 23. (canceled)